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¹ Department of Immunology, ² Clinical Sciences Division, ³ Department of Biochemistry, and ⁴ Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
⁵ Division of Experimental Medicine and ⁶ HIV/AIDS Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94110
⁷ Canadian Immunodeficiency Research Collaborative, ⁸ Maple Leaf Medical Clinic, Toronto, ON M5B 1L6, Canada
⁹ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
¹⁰ Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada

CORRESPONDENCE Brad Jones: brad.jones{at}utoronto.ca; OR Mario Ostrowski: mario.ostrowski{at}gmail.com

Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8⁺ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4⁺ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8⁺ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction.

R.B. Jones and L.C. Ndhlovu contributed equally to this paper.

© 2008 Jones et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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